Synergistic antihypertensive effects of nifedipine on endothelium - Concurrent release of NO and scavenging of superoxide

Recent studies have suggested that part of the vasorelaxation caused by nif edipine, a 1,4-dihydropyridine Ca2+ antagonist, depends on the endothelium. To study the effect of endothelium-dependent vasorelaxation, the release o f NO and superoxide (O-2(-)) in the presence of nifedipine in isolated cult ured rabbit endothelial cells was measured. Highly sensitive electrochemica l microsensors were placed onto the cell membrane, and the kinetics of NO a nd O-2(-) were measured simultaneously with time resolutions of 0.1 and 0.0 5 ms, respectively. Nifedipine at its therapeutical concentrations stimulat ed NO release and scavenged O-2(-) in endothelial cells. The linear relatio nship between NO concentration and nifedipine concentration was observed in the range between 0.01 and 1 nmol/L, NO concentration reached a maximum of 200+/-10 nmol/L at 1.2 nmol/L of nifedipine. The NO concentration was appr oximate to 50% and 30% of the concentration measured in the presence of rec eptor-dependent (acetylcholine) and the receptor-independent (Ca2+ ionophor e A23187) NO synthase (eNOS) agonists, respectively. NO release stimulated by eNOS agonists was followed by the generation of the NO scavenger superox ide. The concentration of O-2(-) was significantly lower after stimulation with nifedipine (peak 5+/-0.5 nmol/L) than after stimulation with acetylcho line (15+/-1 nmol/L) and Ca2+ ionophore (25+/-1 nmol/L). The average rate o f NO release by nifedipine is relatively slow (17 nmol/L per second). This is in sharp contrast to the fast rate of NO release by acetylcholine and Ca 2+ ionophore (40 and 300 nmol/L per second, respectively). These experiment s show that nifedipine, apart from its well-known Ca2+ antagonistic propert ies in vascular smooth muscle cells, stimulates the release of significant concentration of NO in endothelium and also preserves NO concentration. Bot h these effects may be beneficial in the treatment of hypertension.